Cancer-associated fibroblasts (CAFs) are the major cellular stromal component of many solid tumors. In prostate cancer (PCa), CAFs establish a metabolic symbiosis with PCa cells, contributing to cancer aggressiveness through lactate shuttle. In this study, we report that lactate uptake alters the NAD+/NADH ratio in the cancer cells, which culminates with SIRT1-dependent PGC-1α activation and subsequent enhancement of mitochondrial mass and activity. The high exploitation of mitochondria results in tricarboxylic acid cycle deregulation, accumulation of oncometabolites and in the altered expression of mitochondrial complexes, responsible for superoxide generation. Additionally, cancer cells hijack CAF-derived functional mitochondria through the formation of cellular bridges, a phenomenon that we observed in both in vitro and in vivo PCa models. Our work reveals a crucial function of tumor mitochondria as the energy sensors and transducers of CAF-dependent metabolic reprogramming and underscores the reliance of PCa cells on CAF catabolic activity and mitochondria trading.

Cancer-associated fibroblasts promote prostate cancer malignancy via metabolic rewiring and mitochondrial transfer / Ippolito, Luigi; Morandi, Andrea; Taddei, Maria Letizia; Parri, Matteo; Comito, Giuseppina; Iscaro, Alessandra; Raspollini, Maria Rosaria; Magherini, Francesca; Rapizzi, Elena; Masquelier, Julien; Muccioli, Giulio G; Sonveaux, Pierre; Chiarugi, Paola; Giannoni, Elisa. - In: ONCOGENE. - ISSN 0950-9232. - ELETTRONICO. - 38:(2019), pp. 5339-5355. [10.1038/s41388-019-0805-7]

Cancer-associated fibroblasts promote prostate cancer malignancy via metabolic rewiring and mitochondrial transfer

Ippolito, Luigi;Morandi, Andrea;Taddei, Maria Letizia;Parri, Matteo;Comito, Giuseppina;ISCARO, ALESSANDRA;Raspollini, Maria Rosaria;Magherini, Francesca;Rapizzi, Elena;Chiarugi, Paola;Giannoni, Elisa
2019

Abstract

Cancer-associated fibroblasts (CAFs) are the major cellular stromal component of many solid tumors. In prostate cancer (PCa), CAFs establish a metabolic symbiosis with PCa cells, contributing to cancer aggressiveness through lactate shuttle. In this study, we report that lactate uptake alters the NAD+/NADH ratio in the cancer cells, which culminates with SIRT1-dependent PGC-1α activation and subsequent enhancement of mitochondrial mass and activity. The high exploitation of mitochondria results in tricarboxylic acid cycle deregulation, accumulation of oncometabolites and in the altered expression of mitochondrial complexes, responsible for superoxide generation. Additionally, cancer cells hijack CAF-derived functional mitochondria through the formation of cellular bridges, a phenomenon that we observed in both in vitro and in vivo PCa models. Our work reveals a crucial function of tumor mitochondria as the energy sensors and transducers of CAF-dependent metabolic reprogramming and underscores the reliance of PCa cells on CAF catabolic activity and mitochondria trading.
2019
38
5339
5355
Goal 3: Good health and well-being for people
Ippolito, Luigi; Morandi, Andrea; Taddei, Maria Letizia; Parri, Matteo; Comito, Giuseppina; Iscaro, Alessandra; Raspollini, Maria Rosaria; Magherini, Francesca; Rapizzi, Elena; Masquelier, Julien; Muccioli, Giulio G; Sonveaux, Pierre; Chiarugi, Paola; Giannoni, Elisa
File in questo prodotto:
File Dimensione Formato  
Ippolito et al Oncogene 2019.pdf

Accesso chiuso

Tipologia: Pdf editoriale (Version of record)
Licenza: Tutti i diritti riservati
Dimensione 5.77 MB
Formato Adobe PDF
5.77 MB Adobe PDF   Richiedi una copia
558080.full.pdf

accesso aperto

Tipologia: Preprint (Submitted version)
Licenza: Open Access
Dimensione 29.52 MB
Formato Adobe PDF
29.52 MB Adobe PDF

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1157311
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 156
  • ???jsp.display-item.citation.isi??? 151
social impact